12-substituted steroids



Patented Oct. 27, 1970 3,536,736 IZ-SUBSTITUTED STEROIDS Patrick A. Diassi, Westfield, N.J., assignor to E. R. Squibb & Sons, Inc., New York, N.Y., a corporation of Delaware No Drawing. Filed Sept. 19, 1966, Ser. No. 580,215 Int. Cl. C07c 169/32 US. Cl. 260397.45 8 Claims ABSTRACT OF THE DISCLOSURE Disclosed herein are steroids of the pregnane series having hydroxy or acyloxy substituents in the 11, 12 and 17- positions. These compounds are active as progestational agents.

This invention relates to new steroid chemical compounds and new intermediates in the preparation thereof. More particularly, the invention relates to new steroids of the formula wherein Y, Y and Y may be the same or different and are selected from the group consisting of hydroxy and acyloxy; Y is hydrogen and Y and Y together are x0 (0:); and Z is a single or double bond between C and C11.

The preferred acyloxy radicals are those of hydrocarbon carboxylic acids of less than twelve carbon atoms, as exemplified by the lower alkanoic acids (e.g., acetic, propionic, butyric and tert-pentanoic acid), the lower alkenoic acids, the monocyclic aryl carboxylic acids (e.g., phenylacetic and fl-phenylpropionic acid), the cycloalkane carboxylic acids and the cycloalkene carboxylic acids.

The final products of the invention are physilogically active compounds which possess progestational activity and thus can be employed instead of progesterone, for example, in the treatment of habitual abortion for which purpose they can be administered in the same manner as progesterone, the dosage being adjusted for the relative potency of the particular steroid. The final products of the invention also possess corticoid activity and can be so utilized.

The final products of the invention are prepared by utilizing SB-intermediates having the formula wherein X is halo (preferably chloro or bromo) or hydroxy; X is hydroxy; and X is acyloxy. The final prodnets of the invention may be prepared according to the following equation:

=0 lu-lxz x acyloxy (311: ([3153 X (i=0 OH X=bromo O o X D EH: 0 -X2 CH3 CH3 (5:0 X :0 0 x ---X The process of this invention begins by converting the starting material, a 17a-acyloxy-5/3-pregn 11 cue-3,20- dione, by utilizing a hydrohalic acid such as an N-bromoamide (including imides), for example, N-bromoacetamide or N-bromosuccinimide in the presence of an acid such as perchloric acid, p-toluenesulfonic acid or trichloroacetic acid to yield the 11,B-hydroxy-12u-brom0 compounds of the general Formula B and the 9(11)-dehydro- 12a-hydroxy derivatives, Compound C. Direct bromination of Compound B gives the 45,12a-dibromo Compound D which on dehydrohalogenation by reacting with lithium bromide or lithium chloride in dimethylformamide at elevated temperatures leads to the 4-dehydro Compound E.

Alternatively, Compound D may be prepared by first forming the novel 1lfl,12B-oxide-17a-acyloxy-55-pregna 3,20-dione (Compound B). This is accomplished by treating Compound B with potassium carbonate. Compound B may then be halogenated as above to yield Compound D.

Reacting Compound E with potassium carbonate leads to the 115,125-epoxides of general Formula F.

Compound F, when treated with a hydrogen chloridechloroform solution, yields the corresponding 11 fi,12oz,17mtrihydroxy final products of the invention (Compound G) whereas if Compound F is treated with hydrogen fluoride the corresponding 11B,17ot-diol-12a-acyloxy compounds (Compound H) are recovered.

The 9(11)-dehydro derivative, Compound C, can be brominated to form the 4-bromo-12-hydroxy derivative of Compound C which is then dehydrohalogenated in a manner described for the preparation of Compound E. Compound C may be oxidized with chromic acid to yield an 11-keto-9(11)-dehydro end product.

The starting material of the invention is prepared by reacting 3,3-dimethoxy-5fl-pregn-ll-en-20-one with potassium t-butoxide and oxygen in an organic solvent such as t-butanol. From this reaction mixture are recovered l7ot-hydroxy-5fl-pregn 11 ene-3,20-dione and the new products, 3,3 dimethoxy-l7-hydroxy-55-pregn-11-en-20- one and 17 3-hydroxy-5B,17a-pregn-11-ene-3,20-dione. The l7a-hydroxy-5 3-pregn-l1-en-3,20-dione is acylated in a known manner as by treatment with an acidic anhydride in the presence of an organic acid such p-toluenesulfonic acid to yield the starting material of this invention (Compound A).

The invention may be further illustrated by the following examples:

EXAMPLE 1 3,3-dimethoxy-l7a-hydroxy-5 8-pregn-11-en-20-one; 17ozhydroxy-5p-pregn-11-ene-3,20-dione and 17/8-hydroxy- 5 3,17a-pregn-1 1-ene-3,20-dione To a solution of 10.0 g. of 3,3-dimethoxy-5fl-pregn-11- en-20-one in 124 ml. of benzene is added 139 ml. of 1N potassium t-butoxide in t-butanol and the mixture cooled to about 7 C. A gas measuring burette is attached, the system evacuated, and the mixture stirred under an atmosphere of oxygen. After seven hours the oxygen uptake ceases (@750 ml. absorbed). The reaction mixture is brought to room temperature and 140 ml. of acetic acid followed by 20 g. of zinc dust are added. After stirring for ninety minutes the zinc is filtered and washed with t-butanol. The filtrate is evaporated under reduced pressure to a volume of approximately fifty milliliters and then carefully diluted with water whereupon crystals separate. The crystals are filtered washed with water and dried to give 7.5 g. of 17a-hydroxy-5B-pregn-1l-ene-3,20- dione having a melting point about 200202 C.

From the filtrate, on standing, 3. second crop of crystals is obtained. The crystals are filtered and recrystallized several times from acetone-hexane to give 300 mg. of 17,8-hydroxy-5fl,17a-pregn 11 ene-3,20-di0ne having a 4 melting point about 163175 C., +4.l (chloroform) max. $5 1 4..20(d, d, 2, 9.5 cps, 11-11), 4.40(d, 9.5 cps,

Analysis.Calcd for C H O (330.45) (percent): C, 76.32; H, 9.15. Found (percent): C, 76.32; H, 9.31.

The mother liquor is evaporated under reduced pressure and the residue plate chromatographed on Woelm neutral alumina (Activity V) using chloroform as the developing solvent. The band at Rf 0.5 detectable by iodine vapor is eluted with ethyl acetate, evaporated and crystallized from methanol to give 412 mg. of 3,3-dimethoxy- 17a-hydroxy-5B-pregn-11-en-20-one having a melting point about 152-154" C., [5th, +18.9

3,933,9 3625, 1710 01113 1-% 4.24(br, 11-11 and 12-11 6.81(s, 3-00113), 6.86(s, 3-oo11, 910 3, 19-011 9.26(s, 13-011, 7.71(s, 21-011,

Analysis.-Calcd for C H O (374.50) (percent): C, 73.76; H, 9.15. Found (percent): C, 73.93; H, 9.43.

EXAMPLE 2 12u-bror'no-11p,l7a-dihydroxy-5fl-pregna-3,20 dione 17- acetate and 12a,17a-dihydroxy-5B-pregn-9( 11)-ene-3, 20-dione 2.31, 5.77, 5.33 ,1, fij 5.50011, 113-11),

5.77(d, 2 cps, 125-H), 7.82(s, 21CH3), 7.90(s, 17-OAG), 377(3, 19-CH3), 8.92(s, 13-011,)

AnaIysis.Calcd for C H O Br (469.43) (percent) C, 58.85; H, 7.09; Br, 17.03. Found (percent): C, 58.94; H, 6.79; Br, 17.24.

The mother liquid is evaporated and plate chromatographed on silica gel HF using ethyl acetate-chloroform (1:4, v.v) as the developing solvent. Three bands could be detected by iodine vapor at Rf 0.7, 0.4 and 0.3, respectively. The least polar band on elution and crystallization gives 79 mg. of starting material. The band at Rf=0.4 gives 76 mg. of 12u-brorno-11p, 17a-dihydroxy- 5fl-pregna-3,20-dione 17-acetate and the most polar band gives 294 mg. of 12a,17u-dihydroxy-5 3-pregn-9(ll)-ene- 3,20-dione having a melting point about 222225 C., [a] 128 (chloroform) 2;} 2.30, 5.79, 3.04 .g ggeg 4.57(S, 11-11), 5.04. (br, IZB-H), 7.63 (3, 21-011 7.91 (s, 17OA0), 8.82 (s, 18-CH 9.31 (s, 19CH Analysis.Calcd for C H O (388.49) (percent): C, 71.10; H, 8.30. Found (percent): C, 71.01; H, 8.23.

EXAMPLE 3 11,8,12fl-oxido-17ot-acetoxy-5 3-pregna-3,'20-dione To a suspension of mg. of 12a-br0mo-11,B,175 dihydroxy-5fl-pregna-3,20-dione 17-acetate in 15 ml. of methanol is added 1.5 ml. of 10% potassium carbonate nnie] max.

5 and the mixture stirred at room temperature for ten minutes. It is then neutralized with 10% acetic acid, diluted with water and extracted with chloroform. The chloroform is evaporated to dryness and the residue crystillized from acetone-hexane to give 115,12fl-oxido-17aacetoxy-5fl-pregna-3,20-dione having a melting point about 213-215 C.

EXAMPLE 4 12a-bromo-11B,17a-dihydroxyprogesterone 17-acetate To a solution of 1.93 g. of 12a-brorno-1lB,17a-dihydroxy-Sfi-pregna-SJO-dione l7-acetate in 2-0 ml. of chloroform and 20 ml. of methylene dichloride cooled to C. a 6.0 ml. of a solution containing 110 mg. of bromine and 370 mg. of sodium acetate per milliliter of acetic acid are added dropwise with stirring. The solution is diluted with water and extracted with chloroform. The chloroform is washed well with water, dried over magnesium sulfate and evaporated under reduced pressure. The residue is dissolved in 100 ml. of dimethylformarnide, 10 g. of lithium bromide are added and the mixture heated, under nitrogen, on a steam bath for four hours. After cooling it is diluted with water and extracted with chloroform. The chloroform is washed with water and evaporated under reduced pressure. Crystallization of the residue from acetonehexane gives 1.60 g. of 121x-br0mo- 11B,17a-dihydroxyprogesterone 17-acetate having a melting point about 2Q2-204 C., [a] +53 (chloroform),

335,, 2391115 3311,3 2.97, 5.74, 5.32, 6.01, 6.14,, TS1(CH3)4 4.23 (s, 4-H 5.43 (111, 114-11 5.74

CD012 (d, 2.5 cps, 12fl-H), 7.82 (s, 21CH 7.90

(s, 17-OAc), 8.57 (s, 19CH 8.88 (s, 18CH Analysis.-Calcd for C H O Br (467.38) (percent): C, 59.10; H, 6.69; Br, 17.10. Found (percent): C, 59.08; H, 6.90; Br, 17.56.

EXAMPLE 5 11B,12fi-oxido-17a-hydroxyprogesterone 17-acetate evaporated. Crystallization of the residue from methanol gives 493 mg. of 11,8,1Zfi-oxido-17a-hydroxypr0gesterone 17-acetate having a melting point about 230-232, [u] +97 (chloroform),

33 233 my (6, 163000), 33,333} 5.73, 5.32, 5.99, 614,., 439, 4.24 (s, 4-H 6.50 (d, 4 cps, Ila-H), 6.76 (m, 12a-H), 7.78 (3, 21-0115), 7.89 (s, 17-OAc), 8.63 (s, 19-CH9), 9.24 (s, 18CH Analysis.--Calcd for C H O (386.47) (percent): C, 71.48; H, 7.82. Found (percent) C, 71.71; H, 7.95.

The mother liquor is plate chromatographed on silica gel HF using ethyl acetate-chloroform (1:3, v.v) as the developing solvent. Elution followed by crystallization of the U.V. detectable band at Rf-0.5 gives an additional 306 mg. of 11,8,12fi-oxido-17a-hydroxyprogesterone 17- acetate. Elution of the U.V. detectable band at Rf-0.3 gives on crystallization 135 mg. of 1119,12B-oxido-17a-hydroxyprogesterone having a melting point about 253-255 [a] +134 (chloroform) g, 239 m (6, 16200), xggg 2.37, 5.35, 6.00, 6.18 73153 427 (5, 4-11 6.76 (br, 113-11, 123-11 6.52 (br, 17-OH), 7.61 (s, 21C H 8.64 (s, 19CH 9.16 (s, 13-011,).

6 Analysis.-Calcd for C H O (344.44) (percent): C, 73.22; H, 8.19. Found (percent): C, 73.19; H, 8.29.

EXAMPLE 6 11 [3,12a,17a-trihydroxyprogesterone To a solution of 193 mg. of 11B,12/3-oxido-17a-hydroxy-progesterone 17-acetate in 10 ml. of chloroform cooled to 0 C. are added dropwise over a five-minuteperiod 8.3 ml. of 0.42 N hydrogen chloride in chloroform. After one hour the solution is washed several times with Water and evaporated to dryness under reduced pressure. The residue is plate chromatographed on silica gel HF using ethyl acetate-chloroform (1:4, v.v) as the developing solvent. Elution of the band followed by evaporation and crystallization gives 81 mg. of 11fi,12d,170ttrihydroxyprogesterone having a melting point about 250- 252, [a] +l5l ethanol) 33 ,3, 240 m 6,13550), 39, 3,9 3600, 3435, 1711, 1661, 1600 CHI-1, 33 5 2.90-3.00, 5.34, 6.02, 6.18

Analysis.-Calcd for C H O (362.45) (percent): C, 69.58; H, 8.34. Found (percent): C, 68.70; H, 8.23.

EXAMPLE 7 1 1 3,123, 17a-trihydroxyprogesterone 12rx-acetate (a) From 11,8,12,8-oxido-17a-hydroxyprogesterone -17 acetate.-To a solution of mg. of 11fl,12 3-0Xid0-170thydroxyprogesterone 17-acetate in 5 ml. of chloroform and 1.0 ml. of tetrahydrofuran contained in a polyethylene bottle and cooled to 60 C. are added 1.1 ml. of hydrogen fluoride. The mixture is then stirred at 0 C. for twenty hours then poured into a mixture of 50 ml. of chloroform and 20 ml. of Water contained in a polyethylene beaker. The solution is neutralized with sodium bicarbonate the chloroform is washed with water and evaporated under reduced pressure. Plate chromatography of the residue on silica gel HF using ethyl acetatechloroform (1:1, v.v) as the developing solvent gives a band at Rf-0.2 which on elution with methanol-ethyl acetate (1:3, v.v) followed by evaporation and crystallization from acetone-hexane gives 14 mg. of 115,120, 17a-trihydroxyprogesterone 12u-acetate having a melting point about 196-198", [a] -|-139 (95% ethanol),

max.

.gggg 4.31 S, 4-H 4.35 (d, 2.3 cps, 126-11), 5.92 (111, 114-11 6.16 (s, 17-011 7.33 (3, 21-011,), 3.55 (S, 19-011, 3.97 (3, 13-011,).

EXAMPLE 8 1200, 17 a-dihydroxypregna-4,9 1 1 -diene-3,20-dione 17-acetate Following the procedure of Example 4 but substituting 12u,17u-dihydroxy-5B pregn-9(11) ene-3,20-dione 17- 'acetate for 12m-bromo-1113,17a-dihydroxy-5fi-pregna-3, 20-dione 17-acetate there is obtained 12a,17a-dihydroxypregna-4,9(ll)-diene-3,20-dione l7-acetate having a melting point about 23 8-285", [a] 63 (chloroform),

6.13 ,1, @5 5 424 5, 4-11), 4.60(S, 11-11), 5.10(m, 12 -11 7.63(s, 21-011, 7.94(S, 17-0A6),

Analysis.Caled for C H O (386.47) (percent): C, 71.48; H, 7.82. Found (percent): C, 71.45; H, 7.86.

EXAMPLE 9 l7a-acetoXy-5fl-pregn-9 1 l -ene-3, l 2,2 -tri0ne To a solution of 150 mg. of l2a,17a-dihydroxy-5B- pregn-9(11)-ene-3,20-dione l7-acetate in 4.0 ml. of reagent grade acetone are added dropwise 1.5 ml. of a solution containing 20 mg. of chromic anhydride and 32 mg. of sulfuric acid per milliliter of acetone-water (9:1, v.v). After five minutes the mixture is slowly diluted with water and the crystals which separate are filtered washed with water and dried. Recrystallization from acetone-hexane gives 92 mg. of 17u-acetoxy-5/3-pregn- 9(11)-ene-3,12,20-trione having a melting point about 185-187, [a] -|64 (chloroform),

7955 1 4.0-(5, 11-11), 7.62(s, 21-011,), 739 3, 17-OA0), 373 5, 19-0H, 9.2].(5, 13-011,)

Analysis.-Calcd for C H O (386.47) (percent): C, 71.48; H, 7.82. Found (percent): C, 71.86; H, 7.56.

The invention may be variously otherwise embodied within the scope of the appended claims.

What is claimed is:

1. A compound having the formula:

wherein Y, Y and Y are selected from the group consisting of hydroxy and acyloxy; Y is hydrogen and Y and Y together are OX0 (0 Z is a single or double bond and when Z is a double bond, Y is hydrogen and the 4(5) bond is saturated.

2. A compound having the formula I X C O wherein X is selected from the group consisting of halo and hydroxy, X is hydroxy and X is acyloxy.

3. A compound in accordance with claim 1 having the name 11p,12a,l7a-trihydroxyprogesterone IZa-acetate.

4. A compound in accordance with claim 1 having the name 11p,12a,17a-trihydroxyprogesterone.

5. A compound in accordance with claim 2 having the name 12a-bromo-1118,17a-dihydroxy-5fl-pregna-3,20- dione 17-acetate.

6. A compound having the formula wherein Y Y and Y are as defined in claim 1.

7. A compound in accordance with claim 6 having the name 17a-acetoxy5 ,8-p1'egn-9 1 1 -ene-3, 12,20-trione. 8. A compound in accordance with claim 6 having the name 12a,17a-dihydroxy-5fl-pregn-9( 1 1 -ene-3,20- dione 17-acetate.

References Cited UNITED STATES PATENTS Becker et al., Journ. Org. Chem., vol. 30, July 1965, pp. 2169-2175.

LEWIS GOTIS, Primary Examiner E. G. LOVE, Assistant Examiner US. Cl. X.R. 260-239.55, 999

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No 3 536 736 October 27 1970 Patrick A. Diassi It is certified that error appears in the above identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1 line 47 "physilogically" should read physiologically Column 2, lines 15 to 25, equation at the left side should appear as shown below:

X=bromo Column 3 line 16 "oxide" should read oxido line 29 can he" should read can also be Column 5 line 54 (a 163000) should read (s 16300) same line 54 614W should read 6 14p line 72 "CCCI should read w CDCl Column 7 line 2 "238-285" should read Signed and sealed this 13th day of July 1971 (SEAL) Attest:

EDWARD M.PLETCHER,JR. WILLIAM E. SCHUYLER, JR.

Attesting Officer Commissioner of Patents 

